The overall goal of this project is to define the specific biochemical pathways involved in the metabolism of the two model environmental aldehydes - acrolein and trans-2-hexenal. We propose the specific hypothesis that glutathione S-transferase (GST)-catalyzed conjugation is the key metabolic transformation that detoxifies environmental aldehydes. To test this hypothesis, our first aim is to identify the major murine metabolites of acrolein and hexenal and to delineate the contribution of glutathiolation and mercapturic acid formation to overall aldehyde disposition. Using different routes of administration, we will examine the extent to which cardiovascular tissues are exposed to ingested or inhaled ialdehydes, and whether these aldehyde exposures lead to glutathione depletion and accumulation of protein-aldehyde adducts in cardiovascular tissues. To determine how hypercholestermia affects aldehyde metabolism, we will assess the contribution of serum lipoproteins in removing aldehydes. The second aim of our project is to elucidate the cardiovascular metabolism of aldehydes. For this we will identify and quantify the major aldehyde metabolites generated in cardiovascular tissues, elucidate the biochemical pathways involved in the cardiovascular metabolism of aldehydes and measure the cardiovascular expression and abundance of the aldehyde-metabolizing enzymes - aldose reductase, aldehyde dehydrogenase and cytochrome P450. Our third aim is to assess the contribution of specific GST-isoforms to aldehyde detoxification and cardiovascular toxicity. To test the specific contribution of GST isoforms, we will compare the systemic and cardiovascular metabolism of aldehydes in wild-type, GSTA4- and GSTP1-1-null mice, and determine whether a lack of these enzymes results in the upregulation of other GST proteins or enzymes involved in subsidary aldehyde metabolism. To assess the toxicological significance of GST, we will determine whether these GST-null mice are more sensitive to aldehyde toxicity as defined by Projects II, III, and IV. Finally, to determine the metabolic consequences of aldehyde exposure, we will examine how chronic exposures induce or inactivate specific components of aldehyde metabolism and whether chronic aldehyde treatment inhibits cytochrome P450-mediated metabolism and results in a quantifiable autoimmune response that could be related to the extent of exposure. Completion of this project will provide a better understanding of the metabolic defenses against aldehyde toxicity and the relative susceptibility of cardiovascular tissues to aldehyde-induced injury and dysfunction. Identification of the components of aldehyde metabolism will form the basis of future assessments of the metabolic factors that determine the relative risk and susceptibility to the cardiovascular toxicity of environmental aldehydes.